4-aminobutyrate transaminase
| 4-aminobutyrate transaminase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 4-Aminobutyrate transaminase homodimer, Pig | |||||||||
| Identifiers | |||||||||
| EC no. | 2.6.1.19 | ||||||||
| CAS no. | 9037-67-6 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDBstructures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO/QuickGO | ||||||||
| |||||||||
| 4-aminobutyrate transaminase | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | ABAT | ||||||
| NCBI gene | 18 | ||||||
| HGNC | 23 | ||||||
| OMIM | 137150 | ||||||
| RefSeq | NM_020686 | ||||||
| UniProt | P80404 | ||||||
| Other data | |||||||
| Locus | Chr. 16p13.2 | ||||||
| |||||||
Inenzymology,4-aminobutyrate transaminase(EC2.6.1.19), also calledGABA transaminaseor4-aminobutyrate aminotransferase, or GABA-T,is anenzymethatcatalyzesthechemical reaction:
- 4-aminobutanoate + 2-oxoglutaratesuccinate semialdehyde + L-glutamate
Thus, the twosubstratesof this enzyme are4-aminobutanoate(GABA) and2-oxoglutarate.The twoproductsaresuccinate semialdehydeandL-glutamate.
This enzyme belongs to the family oftransferases,specifically thetransaminases,which transfer nitrogenous groups. Thesystematic nameof this enzyme class is4-aminobutanoate:2-oxoglutarate aminotransferase.This enzyme participates in 5 metabolic pathways: alanine and aspartatemetabolism,glutamate metabolism,beta-alanine metabolism,propanoate metabolism,andbutanoate metabolism.It employs onecofactor,pyridoxal phosphate.
This enzyme is found inprokaryotes,plants,fungi,andanimals(includinghumans).[1]Pigs have often been used when studying how this protein may work in humans.[2]
Enzyme Commission number
[edit]GABA-T isEnzyme Commission number2.6.1.19. This means that it is in thetransferaseclass of enzymes, thenitrogenous transferasesub-class and thetransaminasesub-subclass.[3]As a nitrogenous transferase, its role is to transfernitrogenousgroups from one molecule to another. As a transaminase, GABA-T's role is to move functional groups from anamino acidand aα-keto acid,and vice versa. In the case of GABA-T, it takes a nitrogen group from GABA and uses it to create L-glutamate.
Reaction pathway
[edit]In animals, fungi, and bacteria, GABA-T helps facilitate a reaction that moves anaminegroup from GABA to 2-oxoglutarate, and aketonegroup from 2-oxoglutarate to GABA.[4][5][6]This produces succinate semialdehyde and L-glutamate.[4]In plants,pyruvateandglyoxylatecan be used in the place of 2-oxoglutarate.[7]catalyzed by the enzyme4-aminobutyrate—pyruvate transaminase:
- (1)4-aminobutanoate(GABA) +pyruvate⇌succinate semialdehyde+ L-alanine
- (2) 4-aminobutanoate (GABA) +glyoxylate⇌ succinate semialdehyde +glycine
Cellular and metabolic role
[edit]The primary role of GABA-T is to break down GABA as part of the GABA-Shunt.[2]In the next step of the shunt, the semialdehyde produced by GABA-T will beoxidizedtosuccinic acidbysuccinate-semialdehyde dehydrogenase,resulting in succinate. This succinate will then entermitochondrionand become part of thecitric acid cycle.[8]The critic acid cycle can then produce 2-oxoglutarate, which can be used to make glutamate, which can in turn be made into GABA, continuing the cycle.[8]
GABA is a very importantneurotransmitterin animal brains, and a low concentration of GABA in mammalian brains has been linked to several neurological disorders, includingAlzheimer's diseaseandParkinson's disease.[9][10]Because GABA-T degrades GABA, the inhibition of this enzyme has been the target of many medical studies.[9]The goal of these studies is to find a way to inhibit GABA-T activity, which would reduce the rate that GABA and 2-oxoglutarate are converted to semialdehyde and L-glutamate, thus raising GABA concentration in the brain. There is also a genetic disorder in humans which can lead to a deficiency in GABA-T. This can lead to developmental impairment or mortality in extreme cases.[11]
Inplants,GABA can be produced as a stress response.[5]Plants also use GABA to for internal signaling and for interactions with other organisms near the plant.[5]In all of these intra-plant pathways, GABA-T will take on the role of degrading GABA. It has also been demonstrated that the succinate produced in the GABA shunt makes up a significant proportion of the succinate needed by the mitochondrion.[12]
In fungi, the breakdown of GABA in the GABA shunt is key in ensuring a high level of activity in the critic acid cycle.[13]There is also experimental evidence that the breakdown of GABA by GABA-T plays a role in managing oxidative stress in fungi.[13]
Structural Studies
[edit]There have been severalstructuressolved for this class of enzymes, givenPDBaccession codes, and published in peer-reviewed journals. At least 4 such structures have been solved using pig enzymes:1OHV,1OHW,1OHY,1SF2,and at least 4 such structures have been solved inEscherichia coli:1SFF,1SZK,1SZS,1SZU.There are actually some differences between the enzyme structure for these organisms.E. colienzymes of GABA-T lack an iron-sulfur cluster that is found in the pig model.[14]
Active sites
[edit]Amino acid residues found in theactive siteof 4-aminobutyrate transaminase include Lys-329, which are found on each of the two subunits of the enzyme.[15]This site will also bind with apyridoxal 5'- phosphateco-enzyme.[15]
Inhibitors
[edit]- Aminooxyacetic acid
- Gabaculine
- Phenelzine
- Phenylethylidenehydrazine(PEH)
- Rosmarinic acid[16]
- Valproic acid
- Vigabatrin
References
[edit]- ^"4-aminobutyrate aminotransferase - Identical Protein Groups - NCBI".www.ncbi.nlm.nih.gov.Retrieved2020-09-29.
- ^abIftikhar H, Batool S, Deep A, Narasimhan B, Sharma PC, Malhotra M (February 2017)."In silico analysis of the inhibitory activities of GABA derivatives on 4-aminobutyrate transaminase".Arabian Journal of Chemistry.10:S1267–75.doi:10.1016/j.arabjc.2013.03.007.
- ^"BRENDA - Information on EC 2.6.1.19 - 4-aminobutyrate-2-oxoglutarate transaminase".www.brenda-enzymes.org.Retrieved2020-09-24.
- ^abTunnicliff G (1986). "4-Aminobutyrate Transaminase". In Boulton AA, Baker GB, Yu PH (eds.).Neurotransmitter Enzymes.Vol. 5. pp. 389–420.doi:10.1385/0-89603-079-2:389.ISBN0-89603-079-2.
- ^abcShelp BJ, Bown AW, Zarei A (2017)."4-Aminobutyrate (GABA): a metabolite and signal with practical significance".Botany.95(11): 1015–32.doi:10.1139/cjb-2017-0135.hdl:1807/79639.
- ^Cao J, Barbosa JM, Singh N, Locy RD (July 2013). "GABA transaminases from Saccharomyces cerevisiae and Arabidopsis thaliana complement function in cytosol and mitochondria".Yeast.30(7): 279–89.doi:10.1002/yea.2962.PMID23740823.S2CID1303165.
- ^Fait A, Fromm H, Walter D, Galili G, Fernie AR (January 2008). "Highway or byway: the metabolic role of the GABA shunt in plants".Trends in Plant Science.13(1): 14–9.doi:10.1016/j.tplants.2007.10.005.PMID18155636.
- ^abBown AW, Shelp BJ (September 1997)."The Metabolism and Functions of [gamma]-Aminobutyric Acid".Plant Physiology.115(1): 1–5.doi:10.1104/pp.115.1.1.PMC158453.PMID12223787.
- ^abRicci L, Frosini M, Gaggelli N, Valensin G, Machetti F, Sgaragli G, Valoti M (May 2006). "Inhibition of rabbit brain 4-aminobutyrate transaminase by some taurine analogues: a kinetic analysis".Biochemical Pharmacology.71(10): 1510–9.doi:10.1016/j.bcp.2006.02.007.PMID16540097.
- ^Sherif FM, Ahmed SS (April 1995). "Basic aspects of GABA-transaminase in neuropsychiatric disorders".Clinical Biochemistry.28(2): 145–54.doi:10.1016/0009-9120(94)00074-6.PMID7628073.
- ^"GABA-TRANSAMINASE DEFICIENCY".www.omim.org.Retrieved2020-10-18.
- ^Fait A, Fromm H, Walter D, Galili G, Fernie AR (January 2008)."Highway or byway: the metabolic role of the GABA shunt in plants".Trends in Plant Science.13(1): 14–9.doi:10.1016/j.tplants.2007.10.005.PMID18155636.
- ^abBönnighausen J, Gebhard D, Kröger C, Hadeler B, Tumforde T, Lieberei R, et al. (December 2015)."Disruption of the GABA shunt affects mitochondrial respiration and virulence in the cereal pathogen Fusarium graminearum".Molecular Microbiology.98(6): 1115–32.doi:10.1111/mmi.13203.PMID26305050.S2CID45755014.
- ^Liu W, Peterson PE, Carter RJ, Zhou X, Langston JA, Fisher AJ, Toney MD (August 2004)."Crystal structures of unbound and aminooxyacetate-bound Escherichia coli gamma-aminobutyrate aminotransferase".Biochemistry.43(34): 10896–905.doi:10.1021/bi049218e.PMID15323550.
- ^abStorici P, De Biase D, Bossa F, Bruno S, Mozzarelli A, Peneff C, et al. (January 2004)."Structures of gamma-aminobutyric acid (GABA) aminotransferase, a pyridoxal 5'-phosphate, and [2Fe-2S] cluster-containing enzyme, complexed with gamma-ethynyl-GABA and with the antiepilepsy drug vigabatrin".The Journal of Biological Chemistry.279(1): 363–73.doi:10.1074/jbc.M305884200.PMID14534310.S2CID42918710.
- ^Awad R, Muhammad A, Durst T, Trudeau VL, Arnason JT (August 2009). "Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity".Phytotherapy Research.23(8): 1075–81.doi:10.1002/ptr.2712.PMID19165747.S2CID23127112.
Further reading
[edit]- Scott EM, Jakoby WB (April 1959)."Soluble gamma-aminobutyric-glutamic transaminase from Pseudomonas fluorescens".The Journal of Biological Chemistry.234(4): 932–6.doi:10.1016/S0021-9258(18)70206-8.PMID13654294.
- Aurich H (October 1961). "[On the beta-alanine-alpha-ketoglutarate transaminase from Neurospora crassa]" [On the beta-alanine-alpha-ketoglutarate transaminase from Neurospora crassa].Hoppe-Seyler's Zeitschrift für Physiologische Chemie(in German).326:25–33.doi:10.1515/bchm2.1961.326.1.25.PMID13863304.
- Schousboe A, Wu JY, Roberts E (July 1973). "Purification and characterization of the 4-aminobutyrate--2,ketoglutarate transaminase from mouse brain".Biochemistry.12(15): 2868–73.doi:10.1021/bi00739a015.PMID4719123.
- Parviz M, Vogel K, Gibson KM, Pearl PL (November 2014)."Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies"(PDF).Journal of Pediatric Epilepsy.3(4): 217–227.doi:10.3233/PEP-14097.PMC4256671.PMID25485164.
External links
[edit]
- 4-Aminobutyrate+Transaminaseat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- Pearl PL, Parviz M, Hodgeman R, Gibson KM, Reimschisel T (2015)."GABA-transaminase deficiency".MedLink Neurology.
